Alloantibodies in Pediatric Heart Transplantation

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The purpose of this study is to determine the clinical outcomes of sensitized pediatric heart transplant recipients with a positive donor-specific cytotoxicity crossmatch and to compare this group with outcomes in nonsensitized heart transplant recipients.

There is currently a renewed interest in alloantibodies in transplantation. In 1966, Kissmeyer and colleagues reported that pre-existing antibodies directed against donor cells could cause hyperacute rejection of the renal allograft. Three years later, in a landmark study, Patel and Terasaki showed that a lymphocytotoxic assay to identify donor-specific antibodies was highly predictive of acute graft failure. These observations led to the practice of performing prospective, donor-specific crossmatches by lymphocytotoxicity assay for all kidney transplants and for heart and lung transplants when the candidate has a positive panel reactive antibody (PRA) assay. A concept evolved that transplantations should not be performed across a positive cytotoxicity crossmatch. The purpose of this study is to determine the clinical outcomes of sensitized pediatric heart transplant recipients with a positive donor-specific cytotoxicity crossmatch and to compare this group with outcomes in nonsensitized heart transplant recipients.

This study plans to enroll 370 pediatric heart transplant recipients over a period of 3 years. The follow-up period will last up to 3 years. All participants will be enrolled pretransplant. In the pretransplant phase, visits will occur every 6 months. These routine visits will continue until transplant or the end of the study. They will coincide with routine pretransplant status visits. At the time of transplant, the participants will be assigned to one of two groups. Group A will include participants who are allo-antibody negative (less than 10% by AHG CDC-PRA and ELISA in all DTT-treated serum samples). Cohort B will include participants who have the presence of a DTT-treated AHG CDC-PRA of greater than or equal to 10% and/or an ELISA-PRA greater than or equal to 10% in any pretransplant sample.

Both cohorts will receive standard transplantation care. This study has no interventions. All participants will undergo regular blood tests, and, those in the sensitized group will have additional blood testing performed after the transplant and lasting until the end of the study. Post-transplant visits will occur while participants are recovering in the hospital; at Months 1, 3, and 6; and annually until the study closes.

The information collected for the study include data from a physical exam, routine testing, adverse (AEs) and serious adverse (SAEs) events assessments, and blood collection. Each time a biopsy is done, the study will ask to review the biopsy tissue and to collect a sample. If stored tissue is not available, none will be collected.

Cohort A will include participants who are alloantibody Luminex(TM) LABScreen. There is no study mandated care or treatment. All care given is clinical site standard of care. All sites follow a similar standard of care regimen. Non-sensitized recipients receive steroid-free maintenance immunosuppression:

Induction Therapy (anti-T cell antibody induction)

Tacrolimus (Prograf®)

Mycophenolate Mofetil- MMF (CellCept®).

Drug: Induction Therapy

Per standard of care guidelines for immunosuppression at each clinical site.

Other Name: anti-T cell antibody induction

Drug: Tacrolimus

Per standard of care guidelines for immunosuppression at each clinical site.

Other Name: Prograf®

Drug: Mycophenolate Mofetil

Per standard of care guidelines for immunosuppression at each clinical site.

Other Names:

CellCept®

MMF

Cohort B: Sensitized

Cohort B will include participants who are alloantibody positive (Sensitized) as determined by Luminex LabScreen for Class I or Class II with specificities identified by single antigen testing.

There is no study mandated care or treatment. All care given is clinical site standard of care. All sites follow a similar standard of care regimen.

Sensitized recipients receive:

Induction Therapy (anti-T cell antibody induction)

Intraoperative plasma exchange/pheresis

Short-term post-operative plasmapheresis

Post-transplant course of intravenous immunoglobulin (IVIG) therapy

Maintenance corticosteroids (Prednisone)

Tacrolimus (Prograf®)

Mycophenolate Mofetil-MMF (CellCept®).

Drug: Induction Therapy

Per standard of care guidelines for immunosuppression at each clinical site.

Other Name: anti-T cell antibody induction

Drug: Tacrolimus

Per standard of care guidelines for immunosuppression at each clinical site.

Other Name: Prograf®

Drug: Mycophenolate Mofetil

Per standard of care guidelines for immunosuppression at each clinical site.

Other Names:

CellCept®

MMF

Procedure: Intraoperative plasma exchange/pheresis

Per standard of care guidelines for immunosuppression at each clinical site.

Other Name: plasmapheresis

Procedure: Short-term post-operative plasmapheresis

Per standard of care guidelines for immunosuppression at each clinical site.

Other Name: pheresis

Drug: Immunoglobulins, Intravenous

Post-transplant course of intravenous immunoglobulin therapy per standard of care guidelines for immunosuppression at each clinical site.

Other Name: IVIG

Drug: Prednisone

Maintenance corticosteroids per standard of care guidelines for immunosuppression at each clinical site.

This is a composite outcome of death, graft loss or rejection with hemodynamic compromise.

Rejection was considered to be with hemodynamic compromise if the rejection event had new onset echocardiographically measured from fractional shortening <26% with ≥5% fall from last echocardiogram or the rejection event had new onset of heart failure.

Secondary Outcome Measures :

Time to Production of Post-Transplant de Novo Donor-specific Alloantibodies [ Time Frame: Transplantation to first year post transplant (up to 12 months post transplant). ]

Time (in days) from transplant to development of de novo donor-specific alloantibodies (DSA). This measure is calculated as time from transplant until the earliest time of development of any de novo DSA. The DSA is a newly developed alloantibody that is against the donor organ. Alloantibodies are important mediators of acute and chronic rejection.

Percentage of Participants Positive for de Novo Donor-Specific Alloantibody Production in the First Year Post-Transplantation [ Time Frame: Transplantation to first year post transplant (up to 12 months post transplant). ]

A de novo donor-specific alloantibody (DSA) is a newly developed alloantibody that is against the donor organ. This measure includes all de novo DSA (≥1000 MFI) regardless of is persistence or timing within the first year post-transplant. Alloantibodies are important mediators of acute and chronic rejection.

Percentage of Participants- Mortality While on Transplantation Wait-List [ Time Frame: Pre-transplantation ]

Death that occurred while on the transplantation wait-list, and thus before receiving a heart transplant.

Time From Participant Listing on Organ Wait-List to Receiving Organ Transplant, Death or De-Listing [ Time Frame: Study enrollment to transplantation ]

Time (in days) from listing on the organ wait-list to receiving an organ transplant, death or de-listing. This measure is calculated as time from listing on the organ wait-list until the earliest time among transplantation, death and de-listing.

Percentage of Participants With the Presence of Anti-HLA IgG Antibodies by Luminex SA Testing [ Time Frame: Pre-transplantation ]

Luminex SA testing was used to detect the presence of anti-HLA IgG Antibodies for all samples at a central laboratory.

Quantification of anti-HLA IgG antibodies is measured in mean fluorescence intensity (MFI). The maximum MFI for the given subject is provided.

Percentage of Participants With the Presence of Anti-MICA Antibodies by Luminex TM Assay [ Time Frame: Pre-Transplantation ]

Major histocompatibility complex class I chain-related gene A (MICA) is an antigen that is a potential marker of rejection. Luminex TM assay was used to detect its presence.

Percentage of Participants -Overall Participant and Graft Survival [ Time Frame: Transplantation to the end of study (up to 4 years post transplant). ]

This measure looks at the participants who did not die and/or did not receive a subsequent heart transplant.

Presence of C4d on Endomyocardial Biopsy (EMB) [ Time Frame: Transplantation to the end of study (up to 4 years post transplant). ]

The biopsy of the heart stained positive for the presence of C4d, a potential marker of rejection.

Percentage of Participants With Occurrence of Re-Hospitalization(s) [ Time Frame: Transplantation to the end of study (up to 4 years post transplant). ]

Hospitalization is defined as any hospitalization lasting greater than 24 hours.

Percentage of Participants Positive for Severe Infection(s) [ Time Frame: Transplantation to the end of study (up to 4 years post transplant). ]

Severe infections are defined as a clinical illness considered likely infectious in origin that leads to hospitalization.

Time to Diagnosis of Chronic Rejection [ Time Frame: Transplantation to the end of study (up to 4 years post transplant). ]

Time (in days) to the diagnosis of chronic rejection. Chronic rejection is defined as stenosis, irregularity, or ectasia of the epicardial vessels, or severe peripheral pruning of the distal coronary artery tree. Time to diagnosis is time from transplantation until the first diagnosis of chronic rejection.

Time to Post-Transplantation Lymphoproliferative Disorder [ Time Frame: Transplantation to the end of study (up to 4 years post transplant). ]

Time (in days) post-transplant lymphoproliferative disorder (PTLD). PTLD is defined as histopathological evidence of lymphoid proliferation (nodal or extranodal) fulfilling the criteria of the revised classification of the WHO 2008 (Swerdlow 2008). Time to PTLD is time from transplantation until the diagnosis of PTLD.

Time to New-Onset Diabetes Mellitus [ Time Frame: Transplantation to the end of study (up to 4 years post transplant). ]

Time (in days) to new-onset diabetes mellitus. New-onset diabetes mellitus is defined as the new onset of insulin dependency or the need for oral hypoglycemic agents lasting more than 30 days post-transplant. Time to new-onset diabetes is time from transplantation until the diagnosis of new-onset diabetes.

Percentage of Participants Experiencing Acute Rejection [ Time Frame: Transplantation to the end of study. ]

Acute rejection is defined as any one of the following types of rejection: acute cellular rejection (International Society for Heart and Lung Transplant (ISHLT)) system for grading rejection grade 2R or greater), acute refractory cellular rejection (acute cellular rejection unresponsive to two sequential courses of corticosteroids), acute antibody mediated rejection (histological evidence of unequivocal acute capillary injury, with complement deposition and margination of macrophages with or without neutrophils), acute mixed rejection (evidence of acute antibody mediated rejection with ISHLT grade 1R or greater), or acute clinical rejection (clinically-based acute rejection, no matter the ISHLT grade, leading to an acute augmentation of immunosuppression).

Time to Acute Rejection [ Time Frame: Transplantation to the end of study. ]

Time (in days) to acute rejection. Acute rejection is defined as any one of the following types of rejection: acute cellular rejection (International Society for Heart and Lung Transplant (ISHLT) system for grading rejection grade 2R or greater), acute refractory cellular rejection (acute cellular rejection unresponsive to two sequential courses of corticosteroids), acute antibody mediated rejection (histological evidence of unequivocal acute capillary injury, with complement deposition and margination of macrophages with or without neutrophils), acute mixed rejection (evidence of acute antibody mediated rejection with ISHLT grade 1R or greater), or acute clinical rejection (clinically-based acute rejection, no matter the ISHLT grade, leading to an acute augmentation of immunosuppression). Time to acute rejection is time from transplantation to first acute rejection date.

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Inability or unwillingness of the participant or parent/guardian to give written informed consent or comply with the study protocol

Condition or characteristic which in the opinion of the investigator makes the participant unlikely to complete at least one year of follow-up

Current participation in other research studies that would, or might, interfere with the scientific integrity or safety of current study (e.g. by interference with immunosuppression management guidelines, study endpoints, excessive blood draws or SAE evaluation).